Medicament preparation and process for the manufacture thereof

ABSTRACT

HORMONAL IMBALANCE CAN BE FAVORABLY INFLUENCED BY THE ORAL ADMINSTRATION OF SULPHO-CONJUGATED NEUTRAL STERIODS IN GASTRIC-JUICE-RESISTANT FORM.

United States Patent 3,600,495 MEDICAMENT PREPARATION AND PROCESS FOR THE MANUFACTURE THEREOF George W. Oertel, Mainz, Germany, and Kurt Munzel, Riehen, Switzerland, assignors to Hotlmann-La Roche Inc., Nutley, NJ.

No Drawing. Filed July 15, 1968, Ser. No. 744,675 Claims priority, application Switzerland, July 28, 1967, 10,755/ 67 Int. Cl. Afilk 17/00 US. Cl. 42431 8 Claims ABSTRACT OF THE DISCLOSURE Hormonal imbalance can be favorably influenced by the oral administration of sulpho-conjugated neutral steroids in gastric-juice-resistant form.

BACKGROUND OF THE INVENTION Disturbances of the normal hormonal equilibrium in warm-blooded mammals is manifested by various diseases and disturbances of varying degrees of severity. For example, in the climacteric, including the preand postclimacteric periods, the symptoms and/ or the corresponding pathological deficiencies Which occur are attributable to a disturbance of the hormonal equilibrium. Decreasing vitality With increasing age is likewise attributable to a disturbance in the normal hormonal equilibrium. Some dematological manifestations are also hormone-dependent, for example, hirsutism seems to be caused by a hormonal imbalance. Many attempts have been made to return the hormonal equilibrium to normal or to alleviate hormonal imbalance by medical means, particularly by exogenous supplying to the organism those hormones whose absence causes the symptoms attributed to the hormonal imbalance. However, until the development of the present invention no universally satisfactory solution to this problem has been developed as manifested by the diversity of preparations available. There is, thus, a need for an orally eifective dosage form which is acceptable "Ice mone imbalance can be favorably influenced by the oral administration of sulpho-conjugated neutral steroids in gastric-juice-resistant form. This form of administration ensures a complete and physiological absorption of these conjugates by the organism. In this manner, the disturbed hormonal equilibrium is returned to normal and the consequences of the hormone imbalance are reduced. This is achieved by the natural metabolic transformation of the sulpho-conjugated neutral steroids. Thus, the preferred embodiment of this invention is concerned with a tablet dosage form characterized by a medicament nucleus containing a sulphoconjugated neutral steroid which is coated with a gastric-juice-resistant layer. As used herein, sulphoconjugated neutral steroids mean non-phenolic steroids Which are esterified with sulphuric acid or with sulphuric acid derivatives, i.e., the sulphates or sulphatides of the steroids. Such non-phenolic steroids are, for example, cholesterol, C -steroids such as pregnenolone, desoxycorticosterone, progesterone (in enol form), C -steroids such as dehydro-epi-androsterone, testosterone, C -steroids such as 19-nortestosterone. Particularly preferred compounds useful in the practice of this invention are pregnenolone and dehydro-epi-androsterone in the form of the sulphate or sulphatide.

Sulphates as used herein include both the acidic sulphates and the mixed salts of sulphuric acid with a nontoxic pharmaceutically acceptable cation such as, for example, ammonium, sodium, potassium and calcium. In the case of the sulphatides, the alcoholic part of the ester must be derived from a non-toxic pharmaceutically acceptable monovalent or polyvalent alcohol, e.g., from glycerine or higher fatty alcohols such as palmityl or stearyl alcohol.

The administration of the composition of this invention in unit dosage form is controlled by the particular needs of the patients and by the symptoms and disease being treated as Well as by the specific active substance being used. In one example, a dosage of between about mg. and about 30 mg. of dehydro-epi-androsterone 3- sulphate per day has proven efficacious for influencing menopausal symptoms as it is evident from Table I and II:

TABLE I Menopausal syndrome in controlled trial using dehydro-epi-androsterone-3-sulphate in a dosage of between and mg. per day Before treatment First month Second month Third month Symptoms Severe Med. Mild o Severe Med. Mild 5 Severe Med. Mild Severe Med. Mild 3 Flush 41 l 6 3 12 2 27 10 9 3 16 15 7 2 19 15 Anxlety l 22 0 13 16 7 3 18 23 3 3 11 26 4 2 12 25 Depression 10 1 22 18 6 1 22 31 2 1 9 31 2 0 8 33 Nervousne 23 0 17 11 1O 1 22 18 8 2 17 16 7 2 13 21 Irritabillli 10 3 12 26 7 5 12 27 7 2 10 24 4 2 8 29 Sleeplessness 24 1 14 12 7 0 25 19 2 3 18 20 5 0 18 20 Transpiration 24 4 12 11 8 2 23 18 7 2 14 20 4 3 13 23 Headaches 13 1 11 6 5 1 11 3 2 l 10 30 3 1 6 33 Dizziness 9 16 0 6 1 2 15 33 3 1 8 31 2 1 8 32 Tachycardia. 13 1 17 20 3 0 20 28 3 1 8 31 4 0 8 31 Total- 189 28 124 169 66 17 186 241 46 19 121 244 42 13 113 262 Women. 51 51 43 43 Peroent 37.0 5. 5 24.3 33. 2 12.9 3. 3 36. 5 47. 3 10. 7 4. 4 28 I 56. 8 9. 8 3.0 26. 3 60. 9

for supplying hormones to organisms, e.g. warm-blooded TABLE II mammals.

SUMMARY OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION It has been found, according to this invention, that hor- Exploitation of the data of Table I according to Kupperman, J AMA 171, 1627 (1959) (A) Total symptoms (51 patients) Before Treated Difference Total l. 1, 357 636 721 Percent 46. 9 53.1 Per patient 12. 5 14.1

Total 220 304 Percent 42 58 Per patient. 4. 3 6.0

The manufacture of gastric-juice-resistant composition is conventional. Generally, polyelectrolytes containing carboxyl groups are used. For example, natural lacquers such as keratin, shellac, collophony; cellulose esters containing carboxyl groups, such as acetyl-phthalyl-cellulose, acetyl-succinyl-cellulose; copolymers containing carboxyl groups which contain maleic acid as the acid component, such as copolymers of styrene and maleic acid anhydride, copolymers of butyl partial ester of maleic acid with styrene and small amounts of acrylic acid, copolymers of maleic acid anhydride and vinyl methyl ether; copolymers containing carboxyl groups which contain acrylic acid or methacrylic acid as the acid component, such as copolymers of styrene and methacrylic acid.

The manufacture of the unit dosage form used in this invention is achieved by conventional methods using conventional equipment. Normally, the film-forming material which is resistant to gastric juice is brought into solution by means of a solvent. Any medicinally acceptable solvent in which the film-forming material is soluble can be used for the manufacture of the solution. For example, when cellulose acetate phthalate is used as the gastricjuice-resistant coating material, methylene chloride, usually mixed with a small amount of a lower alkanol, is advantageously used as the solvent. The concentration of the solution used can vary within wide limits. However, it is convenient that the solution contain about 7 to 12 parts by weight of solvent per part by weight of coating material. The coating procedure is conventional. The nucleus, in tablet form, containing the sulpho-conjugated neutral steroid is treated with the solution containing the coating material in a coating drum. By rotation of the coating drum, a thin uniform coating is produced on the tablets. The coated tablets are subsequently dried and this coating-drying process repeated several times until a sufiicient layer of the gastric-juice-resistant coating is present on the tablets to ensure that the tablets will be unaffected by gastric-sjuice.

The invention is illustrated by the following example.

EXAMPLE Dragee nuclei of 75 mg. weight and a diameter of 6 mm. containing 10.0 mg. of sodium dehydro-epi-androsterone sulphate, 50.00 mg. of lactose, 13.50 mg. of corn starch, 1.35 mg. of talc and 0.15 mg. of magnesium stearate per nucleus are formed and coated with a gastricjuice-resistant lacquer layer by using a lacquer solution consisting of parts by weight of cellulose acetate phthalate, 3 parts by weight of triacetin, 10 parts by weight of ethanol and 77 parts by weight of methylene chloride. A suflic'ient resistance to gastric juices is ensured by application of about 25 layers. The coating amounts to about 10 mg. per nucleus. The lacquered nuclei obtained are dried at about 37 C. for 24-36 hours and then dredged until they have an end weight of about mg.

We claim:

1. A pharameutical unit dosage form suitable for oral administration of a sulpho-conjugated neutral steroid compound selected from the group consisting of the sulphates and sulphatides of dehydro-epi-androsterone and pregnenolone comprising a nucleus containing said steroid and a gastric-juice-resistant layer of polyelectrolytes containing carboxyl groups.

2. A composition according to claim 1 wherein said steroid compound is dehydro-epi-androsterone in the form of sulphate.

3. The preparation according to claim 1 wherein said steroid compound is dehydro-epi-androsterone in the form of a sulphatide.

4. The composition according to claim 1 wherein said steroid compound is pregnenolone in the form of a sulphate.

5. The composition according to claim 1 wherein said steroid compound is pregnenolone in the form of a sulphatide.

6. In a method of treating hormone imbalance by the oral administration of a sulpho-conjugated neutral steroid compound selected from the group consisting of the sulphates and sulphatides of dehydro-epi-androsterone and pregnenolone, the improvement which comprises administering said steroid in the form of a tablet nucleus which is coated with a gastric-juice-resistant layer of polyelectrolytes containing carboxyl groups.

7. The method in accordance with claim 6 wherein said steroid compound is selected from the group consisting of dehydro-epi-androsterone, the sulphate thereof and the sulphatide thereof.

8. The method in accordance with claim 6 wherein said steroid compound is selected from the group consisting of pregnenolone, the sulphate thereof and the sulphatide thereof.

References Cited UNITED STATES PATENTS 3/1963 Enz et al 424243X US. Cl. X.R. 42435, 238, 243 

